Project Summary: Postural tachycardia syndrome (POTS) is a debilitating disorder resulting from cardiovascular autonomic dysfunction, has many causes and is very difficult to treat effectively. We are the first to identify the presence of agonist-like autoantibodies to autonomic receptors in these patients. Our preliminary data support a role for these autoantibodies in altered autonomic responsiveness to upright posture. The present study is designed to test the hypothesis that patients with primary POTS harbor functional autoantibodies to adrenergic receptors and the differing allosteric effects of these antibodies on the natural receptor ligands lead to an excessive tachycardia characteristic of POTS. This proposal incorporates translational and mechanistic studies to: 1) define the prevalence, burden, and the in vivo physiological significance of these antibodies in a well-phenotyped and representative cohort of patients with POTS and a matched cohort of healthy control subjects, and to characterize the stability of these autoantibodies over time in affected POTS patients; 2) examine the pathophysiology of POTS in immunized rabbit models expressing specific antibodies; and 3) develop highly selective peptide inhibitors to block the offending autoantibodies. We will use in vitro cell-based bioassays, vessel and cardiomyocyte contraction assays and in vivo animal models to delineate the pathophysiological role of these antibodies in POTS, and to develop and test specific peptide inhibitors for potential diagnostic and therapeutic applications. These studies will provide realistic expectation of new knowledge regarding the etiology of this disabling disorder and lay the foundation for an entirely new paradigm for the treatment of POTS.